TY - JOUR
T1 - Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML
T2 - Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)
AU - Rubio-San-Simón, Alba
AU - van Eijkelenburg, Natasha K.A.
AU - Hoogendijk, Raoull
AU - Hasle, Henrik
AU - Niemeyer, Charlotte M.
AU - Dworzak, Michael N.
AU - Zecca, Marco
AU - Lopez-Yurda, Marta
AU - Janssen, Julie M.
AU - Huitema, Alwin D.R.
AU - van den Heuvel-Eibrink, Marry M.
AU - Laille, Eric J.
AU - van Tinteren, Harm
AU - Zwaan, Christian M.
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2023/11
Y1 - 2023/11
N2 - Background: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. Objective: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. Methods: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1–7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. Results: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration–time profiles were similar to observed in adults. The most prevalent grade 3–4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38–100) in MDS and 50% (95% confidence interval 19–100) in JMML. Conclusions: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. Clinical Trial Registration: EudraCT 2010-022235-10.
AB - Background: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. Objective: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. Methods: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1–7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. Results: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration–time profiles were similar to observed in adults. The most prevalent grade 3–4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38–100) in MDS and 50% (95% confidence interval 19–100) in JMML. Conclusions: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. Clinical Trial Registration: EudraCT 2010-022235-10.
UR - http://www.scopus.com/inward/record.url?scp=85170356183&partnerID=8YFLogxK
U2 - 10.1007/s40272-023-00588-5
DO - 10.1007/s40272-023-00588-5
M3 - Article
C2 - 37695474
AN - SCOPUS:85170356183
SN - 1174-5878
VL - 25
SP - 719
EP - 728
JO - Pediatric Drugs
JF - Pediatric Drugs
IS - 6
ER -